For the past several decades naturally occurring substances and their semi- or fully synthetic analogues have comprised a very important part in maintaining human health. Continuing research into methodology for the rapid and efficient chemical synthesis of these substances is therefore a priority. The aims of this proposal are to invent methods for the synthesis of complex 1,4-dicarbonyl compounds and to use these methods to prepare biologically active natural products. Such targets are exemplified by lomaiviticins A (1) and B (2) shown in Figure 1. This pair of dimeric diazobenzofluorene glycosides demonstrated potent DNA-damaging activity and promising cytotoxic activity. Lomaiviticin A in particular showed IC50 values ranging from 0.01 to 98 ng/mL against a number of cancer cell lines and exhibited a cytotoxicity profile that differed from the known DNA-damaging drugs adriamycin and mitomycin C suggesting an unprecedented mechanism of action. In view of such data, the preparation of these agents must be addressed. In addition, the ideas in this proposal may have broad implications for the synthesis of other complex 1,4-dicarbonyl natural products, possibly facilitating the search for novel medicinal agents and/or the preparation of compounds with proven activity. PUBLIC HEALTH RELEVANCE The relevance of the proposed project to public health is two-fold: it may 1) provide a blueprint for the synthesis of the lomaiviticins, a pair of antitumor antibiotics with incompletely determined but very promising biological activity;and 2) provide a general method for the construction of certain sensitive and complex molecular substructures that are found in many biologically active compounds.